Relapsed B cell lymphomas are incurable with conventional therapies except stem cell transplantation, a toxic treatment modality which salvages only 20-50 percent of patients with recurrent disease. Innovative new treatment approaches are therefore clearly necessary for this disease. This project will evaluate the feasibility, safety, toxicity, and efficacy of treating patients with relapsed follicular lymphomas with autologous CD8+ cytotoxic T lymphocytes (CTL) which have been genetically modified to express a chimeric T cell receptor recognizing the CD2O antigen present on B cell lymphomas. In Aim 1, we will perform preclinical studies transfecting autologous cytotoxic T lymphocytes obtained by apheresis with an scFvFc:lambda chimeric T cell receptor recognizing the CD2O antigen, clone and expand the transfected T cells, and document their specific cytotoxicity for CD2O-expres sing target cells. Comparative analyses will be performed using cytotoxic T cells transfected with alternative chimeric T cell receptors recognizing the CD19 and CD22 antigens. In Aim 2, we will assess the safety, feasibility, and toxicity of infusing ex-vivo expanded autologous CD8+ T cell clones expressing a CD2O-specific scFvFc:lambda chimeric immunoreceptor into patients with relapsed follicular lymphoma in a small Phase I pilot trial. In Aim 3, we will monitor the trafficking of adoptively transferred CD2O-specific CD8+ T cell clones to lymph nodes and other tumor sites and their persistence in vivo using serial quantitative Indium-111 gamma camera imaging, quantitative real time PCR and flow cytometric analyses of blood, bone marrow and lymph nodes. In Aim 4, we will rigorously assess the partial and complete response rates, remission durations, and adverse events induced by treatment with CTL bearing a CD2O-specific chimeric T cell receptor in a Phase II trial planned to accrue 50 patients over 3 years. We anticipate that these studies will document the technical feasibility of this approach, the safety of administering genetically modified T cells and their ability to induce objective remissions in patients who have failed standard chemotherapy.